Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[CH:23]=[C:24]([F:33])[C:25]([O:29][CH:30]([CH3:32])[CH3:31])=[C:26]([F:28])[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:23]=[C:24]([F:33])[C:25]([O:29][CH:30]([CH3:31])[CH3:32])=[C:26]([F:28])[CH:27]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)Oc1c(F)cc(CCl)cc1F
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1c(F)cc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1F
Yield: 76.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.17 g) is alkylated using 5-chloromethyl-1,3-difluoro-2-isopropoxy-benzene (0.15 g; 0.68 mmol) and K2CO3 (0.3 g; 2.16 mmol) at RT for 18 h. After aqueous work-up the crude material (0.27 g) is de-acetylated in hydrochloric acid (30 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(3,5-difluoro-4-isopropoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.20 g) is obtained and used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].N[CH2:14][C:15]1[CH:20]=CC=CN=1.[CH:21]1([O:26][C:27]2[CH:28]=[C:29]([CH:35]3[CH2:40]CNCC3)[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH:21]1([O:26][C:27]2[CH:28]=[C:29]([CH:35]3[CH2:40][CH2:9][N:8]([C:1]([NH:3][CH2:7][C:6]4[CH:20]=[CH:15][CH:14]=[CH:4][N:5]=4)=[O:2])[CH2:12][CH2:11]3)[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NCc1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)NCc3ccccn3)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a magnetically-stirred suspension of 1,1'-carbonyldiimidazole (3.6 mmol, 0.583 g) in dry toluene (20 mL) at 0° C. was added neat 2-(aminomethyl)pyridine (3.6 mmol, 0.371 mL) dropwise over 10 min. The resulting suspension was stirred at room temperature for 30 minutes, then, heated to reflux for 1.25 hours. The oily solution was slowly cooled to room temperature, at which time a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (1.8 mmol, 0.500 g) in toluene (5 mL) was added dropwise over 15 minutes. The resulting suspension was heated to reflux for 4 hours, and the homogenous solution was then cooled to room temperature. The solvent was removed in vacuo, the residue dissolved in EtOAc (200 mL) and washed with 1N NaOH (2×200 mL) and H2O (4×200 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2 : 1 ) EtOAc: 2) 50% EtOAc/MeOH: 3) MeOH) to afford the title compound as a yellow solid, mp=104°-105° C. (0.3 mmol. 0.121 g. 16% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 1.5 h

Procedure:
Ethyl 5-chloroindole-2-carboxylate (1.4 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and benzyl chloride (2.4 ml) were added. The mixture was heated and stirred for 1.5 hours on a hot bath controlled to 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:19) and crystallized from diethyl ether-hexane to obtain the title compound (1.6 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])N(C)C.[CH3:9][C:10]([CH:12](OC)OC)=O.[O-]CC.[Na+].Cl.[CH3:22][NH:23][C:24]([NH2:26])=[NH:25]>C(O)C>[CH3:8][O:7][CH:3]([O:2][CH3:1])[C:12]1[CH:10]=[CH:9][N:26]=[C:24]([NH:23][CH3:22])[N:25]=1
Reactant: COC(OC)C(C)=O
Reactant: CNC(=N)N
Reactant: COC(OC)N(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNc1nccc(C(OC)OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) of pyruvic aldehyde dimethyl acetal was heated at 100° C. for 16 h. Methanol was removed in vacuo to afford a brown oil. To a solution of 15 mL of sodium ethoxide (21% in ethanol, 41 mmol, 1.0 eq.) was added 4.5 g (41 mmol, 1.0 eq.) of methyl guanidine HCl. The mixture was stirred for 10 min before a solution of the above described oil in 15 mL anhydrous ethanol was added. The mixture was heated to reflux for 24 h, allowed to cool to room temperature and filtered. The solvent was removed in vacuo to afford 2-methylaminopyrimidine-4-carboxaldehyde dimethyl acetal (I-10) as a dark brown oil which was used in the next step without further purification
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N.N[C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18]>>[C:17](=[O:19])=[O:18].[C:15]([CH2:16][C:17]([O-:19])=[O:18])([C:20]([OH:22])=[O:21])=[O:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N
Product: O=C([O-])CC(=O)C(=O)O
Product: O=C=O

Procedure:
The present invention provides an enzymatic or microbial bioconversion process that is capable of producing L-amino acids from the corresponding racemic mixture or from purely D-amino acid sources. The invention utilizes a transaminase that is moderately selective in the conversion of D and L amino acids to 2-keto acids, but exhibits absolute stereospecificity in the conversion of 2-keto acids to L-amino acids. Hence, a D amino acid or a D, L mixture of an amino acid can react with a) glucose and ammonia or b) aspartic acid in the presence of a transaminase to produce the corresponding L-amino acid and c) carbon dioxide or d) oxaloacetate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][C:27]#[C:28][CH3:29])[C:21]([N:30]4[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]4)=[N:20][C:19]=3[N:18]([CH2:37][C:38]([O:40]C)=[O:39])[C:16]2=[O:17])[N:5]=1.Cl>O1CCCC1.O.CO>[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][C:27]#[C:28][CH3:29])[C:21]([N:30]4[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]4)=[N:20][C:19]=3[N:18]([CH2:37][C:38]([OH:40])=[O:39])[C:16]2=[O:17])[N:5]=1
Reactant: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of 1 M sodium hydroxide solution are added to a solution of 150 mg of (R)-1-(4-methyl-quinazolin-2-ylmethyl)-3-(methoxycarbonylmethyl )-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine in 6 ml of tetrahydrofuran/water/methanol (1:1:1). The solution is stirred for 1 h at ambient temperature and then neutralised with 1 M hydrochloric acid. The solution is evaporated to dryness and purified by HPLC (YMC-C18) with water/acetonitrile (70:30).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25]>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CN(S(=O)(=O)O)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phospheric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylacetamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.Cl.[S-:10][C:11]#[N:12].[NH4+].NC(N)=S.Cl[CH2:19][CH:20]=O>O.CCO.CCOC(C)=O>[S:10]1[CH:20]=[CH:19][N:12]=[C:11]1[NH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=CCCl
Reactant: Nc1ccc[nH]c1=O
Agent: Cl
Agent: NC(N)=S
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]cccc1Nc1nccs1
Yield: 40 %

Procedure:
To a solution of 3-Amino-1H-pyridin-2-one (2.0 g, 18.7 mmol) in water (2 mL) was added 15% HCl (10 mL, 18 mmol) followed by ammonium thiocyanate (1.5 g, 18 mmol) and the mixture was heated to reflux for two hours. Upon cooling the intermediate thiourea was found to precipitate as a red-brown solid. The mixture was filtered and the solid washed with water (5 mL). To a solution of the thiourea (1.3 g, 7.7 mmol) in EtOH (20 mL) and water (5 mL) was added chloroacetaldehyde (2.3 mL), 16.4 mmol) and the mixture was heated to reflux for four hours. On cooling, the mixture was diluted with EtOAc (30 mL) and washed with 10% NaHCO3 and brine. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (100% EtOAc) to afford the title compound as a pale green solid (1.43 g, 40%): 1H NMR (400 MHz, CDCl3) δ 1.6 (1H, s), 6.45 (1H, t), 6.75 (1H, s), 7.05-7.10 (1H, m), 7.40-7.42 (1H, m), 8.35-8.5 (2H, m); M+H 194.1, M−H 192.1.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C:24]1[C:33]([NH2:34])=[C:32]2[C:27]([C:28](SC)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>CC(O)=O.O1CCOCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][CH:15]=[N:16][C:8]=2[C:7]1[C:2]([C:30]2[N:29]=[CH:28][C:27]3[C:32](=[C:33]([NH2:34])[CH:24]=[CH:25][CH:26]=3)[N:31]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncnc2c(N)c(C)ccc12
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cccc2cnc(-c3ncccc3-c3ncnc4c3ncn4C3CCCCO3)nc12
Reaction time: 6 h

Procedure:
A 250 ml flask was charged with 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2.92 g, 9.74 mmol) and 7-methyl-4-(methylthio)quinazolin-8-amine (2.00 g, 9.74 mmol) along with 20 ml of dioxane. 1.0 M LiHMDS in THF (29.2 ml, 29.2 mmol) was then added dropwise at RT. The reaction was stirred for 6 hrs and then treated with 5 ml of HOAc. The volatiles were removed under vacuum. The residue was dissolved in chloroform and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel eluting with a gradient of 20 to 60% EtOAc in hexanes to give 7-methyl-4-(methylthio)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylquinazolin-8-amine as a yellow solid. MS Found: (ESI pos. ion) m/z 485 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].O[CH2:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]([OH:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:16][CH:14]([CH3:15])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][O:8]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCCCC(CO)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCC1COC(c2ccc(C#N)cc2)OC1C

Procedure:
A mixture of 0.1 mol of p-cyanobenzaldehyde, 0.1 mol of 3-hydroxymethyl-2-octanol, 200 ml of benzene and 150 mg of p-toluenesulfonic acid is boiled under a water separator until the reaction is complete. Usual working-up gives 2-p-cyanophenyl-5-n-pentyl-4-methyl-1,3-dioxane.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:7]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cccc(O)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 70.9 %

Procedure:
3-Hydroxy-2-nitrobenzoic acid (1.83 g) was dissolved in 50 ml of N,N-dimethylformamide, then 1.23 g of 4-methoxyaniline, 2.50 g of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride, 1.35 g of 1-hydroxybenzotriazole and 1.81 ml of triethylamine were added and the mixture was stirred at room temperature for 66 hours. The reaction solution was concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Chloroform was added to the resulting residue and the resulting precipitate was filtered to give 2.04 g of 3-hydroxy-4′-methoxy-2-nitrobenzanilide. The filtrate was purified by silica gel column chromatography using chloroform-methanol (98:2) as an eluting solvent, chloroform was added to the resulting crude product and the resulting precipitate was filtered to give additional 0.24 g of 3-hydroxy-4′-methoxy-2-nitrobenzanilide.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].COC1C=[C:11]2[C:15](=[CH:16]C=1)[C:14](=[O:18])CC2.CI.[Cl-].[NH4+].[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)(C)C.C(OCC)(=O)C>[CH3:2][O:4][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[C:14](=[O:18])[C:15]([CH3:16])([CH3:11])[CH2:29]2
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CC(C)(C)C2=O

Procedure:
7.78 g of potassium t-butoxide was dissolved in 66.3 ml of t-butanol and 150 ml of toluene. Thereafter, 5.00 g of 5-methoxyindanone dissolved in 170 ml of toluene was added dropwise to the reaction solution at room temperature. Approximately 10 minutes later, 4.79 ml of methyl iodide was added to the reaction solution. After completion of the reaction, a saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The organic layer was then dried over anhydrous magnesium sulfate. After the organic layer had been filtered through celite, the drying agent was removed by filtration. Thereafter, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.08 g of 5-methoxy-2,2-dimethylindanone. The obtained product was dissolved in 9 ml of methanesulfonic acid. Then, 2.45 g of methionine was added to the reaction solution, and the obtained mixture was heated to 110° C. After completion of the reaction, a saturated sodium chloride aqueous solution and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The organic layer was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.41 g of the subject compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.F[P-](F)(F)(F)(F)F.[CH2:21]([N+:25]1[CH:29]=[CH:28]N(C)C=1)[CH2:22]CC>C(NCC)C>[CH2:21]([N:25]([CH2:29][CH3:28])[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:22]
Reactant: CCCC[n+]1ccn(C)c1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Product: CCN(CC)c1nn2c(N)nnc2c(C)c1C
Reaction time: 4 h

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 800 mg and 650 mg divided between 2 microwave vessels) was initially charged each dissolved in 12 ml of diethylamine and admixed with 1-butyl-3-methylimidazolium hexafluorophosphate (150 μl). Subsequently, they were placed into the microwave at 180° C. for 4 h. In order to complete the reaction, they were placed again into the microwave at 180° C. for 4 h and then left to stand overnight. The two reaction mixtures were combined in a round-bottom flask and dried. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. F), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 900 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]=[O:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]>C1COCC1.CCCCCCC>[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]([C:9]3[N:8]=[C:7]([Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[CH:10]=3)[OH:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cc2cc(C)cc(C=O)c2o1
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(C)cc(C(O)c3cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n3)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide (1.0 g) in THF (10 ml) was cooled under an Argon atmosphere to −78° C. n-Buthyllithium solution (1.6 M in heptane, 2.37 ml) were added dropwise. After stirring for 1 hr at −78° C. a solution of 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (963 mg) in THF (10 ml) was added dropwise. Stirring was continued for 15 min at −78° C., then the reaction mixture was warmed up to r.t. overnight. After quenching with water, the mixture was extracted with EtOAc. The organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give rac-7-{[2-(tert-butyl-dimethyl-silanyl)-1-dimethylsulfamoyl-1H-imidazol-4-yl]-hydroxy-methyl}-5-methyl-benzofuran-2-carboxylic acid ethyl ester as light yellow amorphous solid; MS (ISP): 522.3 ((M+H)+.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[CH:16]([C:18]([CH2:20][CH3:21])=[O:19])=[CH2:17].C[O-].[Na+]>CO.CCOC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:16][C:18](=[O:19])[CH2:20][CH3:21])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15]
Reactant: COc1ccc2c(c1)CC(CCO)C2=O
Reactant: C=CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)CCC1(CCO)Cc2cc(OC)ccc2C1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
A solution of 2-(2-hydroxyethyl)-5-methoxy-1-indanone (105 mg, 0.51 mmol) in methanol (2.0 mL) at room temperature was treated with ethyl vinyl ketone (EVK, 0.102 mL) and 0.5M sodium methoxide in methanol (0.204 mL, 0.1 mmol). The mixture was stirred in a capped flask and heated in an oil bath at 60° C. for 8 hours. After cooling, the reaction mixture was diluted with EtOAc (25 mL), washed with 0.2N HCl (15 mL), water (15 mL), and brine (15 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indanone (138 mg, 93% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[N:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[CH:35][C:34]=1[F:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[N:38]=[C:37]([C:39]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:40])[CH:36]=[CH:35][C:34]=1[F:42]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
tert-Butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (5.0 mg, 0.015 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.6 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045 mmol) were mixed together and stirred at room temperature for 1 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (XBridge™ preparative C18 30×10 mm 5 μm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4.1 mg, 48%). LCMS calc. for C30H33F3N5O3 (M+H)+: m/z=568.3. Found: 568.1.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: Cc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Product: Cc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 94 %

Procedure:
4.0 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-5-chloroaniline, 1.54 g of pyridine and 1.88 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 4.5 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-5-chloroaniline are obtained as pale yellow needles.